What are the important side effects of PD-1 (Programmed Death-1) antibodies, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), from most common to least common?

Important Side Effects of PD-1 Antibodies: From Most Common to Least Common

PD-1 inhibitors commonly cause immune-related adverse events (irAEs) affecting multiple organ systems, with skin reactions being the most frequent and myocarditis/neurological disorders being the rarest but potentially most serious. 1

Most Common Side Effects

Fatigue (16-37%)

• The most frequently reported adverse event with anti-PD-1/PD-L1 therapy 1
• Only occasionally attributable to hypothyroidism
• Occurs in approximately 49% of patients on nivolumab compared to 39% on chemotherapy 2

Skin Reactions (30-40%)

• Typically develop early in treatment, within the first few weeks 3
• Include:
  • Pruritus (13-23%)
  • Rash/maculopapular rash (15-28%)
  • Vitiligo (9-11%, particularly in melanoma patients)
  • Dermatitis and other skin eruptions 1, 2
• Management depends on severity:
  • Grade 1: Continue therapy with topical emollients and mild topical steroids
  • Grade 2: Consider holding therapy temporarily, use moderate-potent topical steroids
  • Grade 3-4: Hold therapy, start systemic corticosteroids 3

Endocrine Disorders (10-20%)

• Hypothyroidism (11-19%)
• Hyperthyroidism (6-11%)
• Hypophysitis (rare but significant)
• Adrenal insufficiency (rare) 1
• Often require hormone replacement therapy but rarely necessitate discontinuation of PD-1 inhibitor therapy

Gastrointestinal Effects (10-20%)

• Diarrhea (common)
• Colitis (less common but more severe)
• Can progress to intestinal perforation if not properly managed 1
• Severe colitis (grade 3-4) is less common with PD-1 inhibitors compared to CTLA-4 inhibitors like ipilimumab 1

Less Common but Significant Side Effects

Hepatic Toxicity (5-10%)

• Elevated liver enzymes (AST/ALT)
• Hepatitis
• Requires regular monitoring of liver function tests 1, 2

Pneumonitis (3-7%)

• One of the most serious side effects of PD-1 inhibitors 1
• Higher incidence with PD-1 inhibitors compared to PD-L1 inhibitors 4
• Higher incidence compared to conventional chemotherapy (OR=2.35) 5
• Requires prompt recognition and management as it can be life-threatening

Renal Adverse Events (1-2%)

• Increased creatinine
• Nephritis
• Renal failure (rare) 6

Rare but Potentially Severe Side Effects

Neurological Disorders (<1%)

• Peripheral neuropathy
• Guillain-Barré syndrome
• Myasthenia gravis
• Encephalitis 1

Cardiac Toxicity (<1%)

• Myocarditis
• Pericarditis
• Can be fatal if not recognized and treated promptly 5

Other Rare Events

• Pancreatitis (approximately 1%)
• Severe skin reactions like Stevens-Johnson syndrome (rare)
• Sarcoidosis (rare) 4

Important Clinical Considerations

1. Timing of onset:

   • Skin toxicities often appear first, typically within weeks of starting therapy
   • Other irAEs may develop later, with varying timeframes for different organ systems 1

2. Treatment-related mortality:

   • Approximately 0.17-0.7% of patients experience fatal irAEs 6, 1
   • Most commonly due to pneumonitis, myocarditis, or neurologic events

3. Management principles:

   • Grade 1-2 events: Symptomatic management, consider continuing therapy
   • Grade 3-4 events: Hold or permanently discontinue PD-1 inhibitor, initiate corticosteroids
   • Systemic corticosteroids (methylprednisolone or equivalents) are the mainstay of treatment 7
   • Non-steroidal immunosuppressants may be needed for refractory cases

4. Monitoring recommendations:

   • Regular clinical assessment for new symptoms
   • Baseline and periodic thyroid function, liver function, and renal function tests
   • Prompt evaluation of respiratory symptoms to rule out pneumonitis 3

5. Combination therapy considerations:

   • Combination of PD-1 inhibitors with CTLA-4 inhibitors (e.g., nivolumab + ipilimumab) increases the risk of irAEs 1
   • Grade 3-4 adverse events occur in approximately 32% of patients on combination therapy 1

PD-1 inhibitors have revolutionized cancer treatment but require vigilant monitoring for these immune-related adverse events to ensure early detection and appropriate management, which can significantly improve outcomes and quality of life for patients.